Structure, mechanism and regulation of peroxiredoxins

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Abstract

Peroxiredoxins (Prxs) are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels which mediate signal transduction in mammalian cells. Prxs can be regulated by changes to phosphorylation, redox and possibly oligomerization states. Prxs are divided into three classes: typical 2-Cys Prxs; atypical 2-Cys Prxs; and 1-Cys Prxs. All Prxs share the same basic catalytic mechanism, in which an active-site cysteine (the peroxidatic cysteine) is oxidized to a sulfenic acid by the peroxide substrate. The recycling of the sulfenic acid back to a thiol is what distinguishes the three enzyme classes. Using crystal structures, a detailed catalytic cycle has been derived for typical 2-Cys Prxs, including a model for the redox-regulated oligomeric state proposed to control enzyme activity.

Section snippets

Dimers, decamers and redox-dependent oligomerization

The first reports of Prx oligomerization came in the late 1960s, when transmission electron microscopy (TEM) studies of torin, an abundant protein isolated from human erythrocytes, revealed discrete complexes with apparent tenfold symmetry (Fig. 2a) [30]. Later, in the 1980s, bacterial and yeast Prxs were identified based on their antioxidant properties 31, 32. Torin has since been identified as mammalian PrxII, a typical 2-Cys Prx [33]. In the TEM reports, it was observed that under certain

The Prx classes have similar active sites

Since 1998, the crystal structures of six Prxs have been published, including four typical 2-Cys Prxs (PrxI, PrxII, TryP and AhpC 19, 20, 21, 22), one atypical 2-Cys Prx (PrxV [27]) and one 1-Cys Prx (PrxVI [17]) (Fig. 3). These structures reveal Prxs to be very similar, each containing a thioredoxin fold with a few additional secondary-structure elements present as insertions. The most striking differences involve their oligomeric states. The atypical 2-Cys Prxs are monomeric enzymes, whereas

Catalytic cycle for typical 2-Cys Prxs

Some typical 2-Cys Prxs from bacteria 15, 34 (L.B. Poole, unpublished) and human and rat PrxII 13, 27 undergo redox-sensitive oligomerization. These studies revealed that the reduced or overoxidized forms of the enzyme favored the decameric state, whereas the disulfide-bonded forms existed predominantly as dimers. The current ensemble of Prx structures forms the basis of a detailed catalytic cycle that includes the redox-sensitive oligomerization of these 2-Cys Prxs [22], although the precise

Regulation of Prx activity

Prxs have received a great deal of attention recently owing to their role in regulating levels of hydrogen peroxide, an intracellular signaling molecule common to many cytokine-induced signal-transduction pathways 3, 8, 12, 13. As noted above, some Prxs are themselves sensitive to inactivation by hydrogen peroxide and perhaps peroxynitrite through irreversible oxidation of their peroxidatic cysteine. Indeed, regulation of redox signaling through cysteine modification by peroxides and

Conclusions

The ubiquitous Prxs appear to be diverse in function, ranging from antioxidant enzymes to regulators of signal transduction. This diversity is reflected in slight evolutionary modifications in sequence and structure, built around a common peroxidatic active site. The literature within the Prx field is currently focused on their more recently identified roles as regulators of redox-sensitive signaling 3, 8. Although the precise relationship between the peroxidase activity and the oligomeric

Acknowledgements

We thank S. Watabe for the gift of bovine mitochondrial PrxIII used in Fig. 2d and M. Isupov for preparation of Fig. 2c. We also thank P.A. Karplus for helpful discussions. Structural work on bacterial Prxs in the Poole and Karplus laboratories is supported by a grant from the US National Institutes of Health (GM-50389). A grant from the Stiftung Innovation von Rheinland-Pflaz (GZ. 8312–386261/281) to J.R.H. is also acknowledged. L.B.P. is an Established Investigator with the American Heart

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